The overall goals of the proposed phase 1 SBIR project are to investigate the in vivo efficacy and mechanism of action of a novel, first-in-class drug candidate for treating interstitial cystitis/painful bladder syndrome (IC/PBS). IC/PBS is a chronic and debilitating bladder disorder characterized by severe pain and urinary urgency and frequency. It afflicts about one million individuals in the US, most of who are women. Current treatment options are limited and often ineffective. However, the development of new therapies has been complicated by a poor understanding of the pathogenesis of the disease and by the lack of reliable diagnostic tests. Dr. Susan Keay at the University Of Maryland School Of Medicine has identified an endogenous glycopeptide known as Antiproliferative Factor (APF) in the urine of patients with IC/PBS. APF potently inhibits epithelial cell proliferation in vitro and is believed to play a major role in the pathogenesis of IC by preventing the regenerative healing of the bladder epithelium in IC/PBS patients. Based on this discovery, an analog of APF has been engineered that is an antagonist of APF activity. It normalizes the proliferation of bladder epithelial cells from IC patients in vitro and also overcomes the effect of APF on tight junction protein expression and paracellular permeability. The proposed Phase 1 SBIR project will help to determine the potential for further development of this APF analog as a treatment for IC/PBS and will assist in the design of a screening assay to identify potential new drugs to treat the disease. The ability of the candidate compound to normalize bladder epithelial properties in a mouse model of IC/PBS will be investigated. In addition, the mechanism of action of the compound will be evaluated using flow cytometry. In the Phase 2 SBIR project, these studies will be extended by analyzing the in vivo efficacy of this compound under a wider range of dosing conditions. Preclinical safety studies will also be carried out in Phase 2. An additional Phase 2 focus would be the design and validation of a high-throughput screening assay for identifying APF antagonists, using an appropriate cell line that expresses the receptor for APF. Following Phase 2, an IND will be filed to support a Phase I clinical study. Future clinical development of this APF antagonist would involve enrolling patients with detectable APF in their urine, thus focusing the treatment on individuals most likely to respond, potentially overcoming the historic problem of diagnosis of IC, a disease that may have more than one etiology. PUBLIC HEALTH RELEVANCE: The overall goals of this Phase I SBIR project are to evaluate the in vivo activity and mechanism of action of a novel therapeutic for interstitial cystitis/painful bladder syndrome (IC/PBS). IC/PBS is a chronic and debilitating bladder disorder characterized by severe pain and urinary urgency and frequency. There is a significant need for more effective therapies for this disease.